Submissions for variant NM_000335.5(SCN5A):c.1705C>G (p.Arg569Gly)

dbSNP: rs199473576

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000183172	SCV000235589	uncertain significance	not provided	2022-09-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32233023, 30662450, 25904541)
Color Diagnostics, LLC DBA Color Health	RCV001842935	SCV001348371	uncertain significance	Cardiac arrhythmia	2023-09-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 569 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has reported that this variant together with p.Gln1077del affects sodium channel function (PMID: 25904541). This variant has been reported in an individual affected with Wolff-Parkinson-White syndrome (PMID: 32233023). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002408802	SCV002715806	uncertain significance	Cardiovascular phenotype	2021-12-01	criteria provided, single submitter	clinical testing	The p.R569G variant (also known as c.1705C>G), located in coding exon 11 of the SCN5A gene, results from a C to G substitution at nucleotide position 1705. The arginine at codon 569 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in a Wolf-Parkinson-White cohort; however, clinical details were limited (Coban-Akdemir ZH et al. Am J Med Genet A, 2020 06;182:1387-1399). Additionally, in vitro studies demonstrated that this alteration may have a deleterious effect on protein function (Kapplinger JD et al. Circ Cardiovasc Genet, 2015 Aug;8:582-95). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002492820	SCV002791304	uncertain significance	Brugada syndrome 1; Long QT syndrome 3; Sick sinus syndrome 1; Progressive familial heart block, type 1A; Ventricular fibrillation, paroxysmal familial, type 1; Dilated cardiomyopathy 1E; SUDDEN INFANT DEATH SYNDROME; Atrial fibrillation, familial, 10	2021-09-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000183172	SCV002969291	uncertain significance	not provided	2022-08-20	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 569 of the SCN5A protein (p.Arg569Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of SCN5A-related conditions (PMID: 30662450, 32233023). ClinVar contains an entry for this variant (Variation ID: 201576). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). Experimental studies have shown that this missense change affects SCN5A function (PMID: 25904541). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV001842935	SCV004837504	uncertain significance	Cardiac arrhythmia	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 569 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has reported that this variant together with p.Gln1077del affects sodium channel function (PMID: 25904541). This variant has been reported in an individual affected with Wolff-Parkinson-White syndrome (PMID: 32233023). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656205	SCV000678399	likely pathogenic	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome